At therapeutic doses, amphetamine causes emotional and cognitive effects such as euphoria, change in desire for sex, increased wakefulness, and improved cognitive control. It induces physical effects such as improved reaction time, fatigue resistance, and increased muscle strength. Larger doses of amphetamine may impair cognitive function and induce rapid muscle breakdown. Drug addiction is a serious risk with large recreational doses but is unlikely to arise from typical long-term medical use at therapeutic doses. Very high doses can result in psychosis (e.g., delusions and paranoia) which rarely occurs at therapeutic doses even during long-term use. Recreational doses are generally much larger than prescribed therapeutic doses and carry a far greater risk of serious side effects.[sources 3]

Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD.[55][56][57]Randomized controlled trials of continuous stimulant therapy for the treatment of ADHD spanning 2 years have demonstrated treatment effectiveness and safety.[55][57] Two reviews have indicated that long-term continuous stimulant therapy for ADHD is effective for reducing the core symptoms of ADHD (i.e., hyperactivity, inattention, and impulsivity), enhancing quality of life and academic achievement, and producing improvements in a large number of functional outcomes[note 5] across 9 categories of outcomes related to academics, antisocial behavior, driving, non-medicinal drug use, obesity, occupation, self-esteem, service use (i.e., academic, occupational, health, financial, and legal services), and social function.[56][57] One review highlighted a nine-month randomized controlled trial of amphetamine treatment for ADHD in children that found an average increase of 4.5 IQ points, continued increases in attention, and continued decreases in disruptive behaviors and hyperactivity.[55] Another review indicated that, based upon the longest follow-up studies conducted to date, lifetime stimulant therapy that begins during childhood is continuously effective for controlling ADHD symptoms and reduces the risk of developing a substance use disorder as an adult.[57]

Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems;[58] these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the noradrenergic projections from the locus coeruleus to the prefrontal cortex.[58] Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.[26][58][59] Approximately 80% of those who use these stimulants see improvements in ADHD symptoms.[60] Children with ADHD who use stimulant medications generally have better relationships with peers and family members, perform better in school, are less distractible and impulsive, and have longer attention spans.[61][62] The Cochrane Collaboration's reviews[note 6] on the treatment of ADHD in children, adolescents, and adults with pharmaceutical amphetamines stated that while these drugs improve short-term symptoms, they have higher discontinuation rates than non-stimulant medications due to their adverse side effects.[64][65] A Cochrane Collaboration review on the treatment of ADHD in children with tic disorders such as Tourette syndrome indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine could exacerbate tics in some individuals.[66]

Side effects

The side effects of amphetamine are many and varied, and the amount of amphetamine used is the primary factor in determining the likelihood and severity of side effects.[28][39][40] Amphetamine products such as Adderall, Dexedrine, and their generic equivalents are currently approved by the USFDA for long-term therapeutic use.[36][39]Recreational use of amphetamine generally involves much larger doses, which have a greater risk of serious side effects than dosages used for therapeutic reasons.[40]

Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths.[40] In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident.[40] Amphetamine also induces contraction in the urinary bladder sphincter, the muscle which controls urination, which can result in difficulty urinating.[40] This effect can be useful in treating bed wetting and loss of bladder control.[40] The effects of amphetamine on the gastrointestinal tract are unpredictable.[40] If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system);[40] however, amphetamine may increase motility when the smooth muscle of the tract is relaxed.[40] Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opioids.[2][40]

Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic doses,[64][97] meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine.[97][98]

Overdose

An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.[2][86][99] The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine.[40][86] Tolerant individuals have been known to take as much as 5 grams of amphetamine in a day, which is roughly 100 times the maximum daily therapeutic dose.[86] Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma.[28][40] In 2013, overdose on amphetamine, methamphetamine, and other compounds implicated in an "amphetamine use disorder" resulted in an estimated 3,788 deaths worldwide (3,425–4,145 deaths, 95% confidence).[note 10][100]

Pathological overactivation of the mesolimbic pathway, a dopamine pathway that connects the ventral tegmental area to the nucleus accumbens, plays a central role in amphetamine addiction.[101][102] Individuals who frequently overdose on amphetamine during recreational use have a high risk of developing an amphetamine addiction, since repeated overdoses gradually increase the level of accumbalΔFosB, a "molecular switch" and "master control protein" for addiction.[103][104][105] Once nucleus accumbens ΔFosB is sufficiently overexpressed, it begins to increase the severity of addictive behavior (i.e., compulsive drug-seeking) with further increases in its expression.[103][106] While there are currently no effective drugs for treating amphetamine addiction, regularly engaging in sustained aerobic exercise appears to reduce the risk of developing such an addiction.[107][108] Sustained aerobic exercise on a regular basis also appears to be an effective treatment for amphetamine addiction;[sources 9] exercise therapy improves clinical treatment outcomes and may be used as a combination therapy with cognitive behavioral therapy, which is currently the best clinical treatment available.[107][109][110]

Addiction is a serious risk with heavy recreational amphetamine use but is unlikely to arise from typical long-term medical use at therapeutic doses.[43][44][45]Drug tolerance develops rapidly in amphetamine abuse (i.e., a recreational amphetamine overdose), so periods of extended use require increasingly larger doses of the drug in order to achieve the same effect.[120][121]

ΔJunD, a transcription factor, and G9a, a histone methyltransferase enzyme, both oppose the function of ΔFosB and inhibit increases in its expression.[104][123][128] Sufficiently overexpressing ΔJunD in the nucleus accumbens with viral vectors can completely block many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).[123] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[106][123][129] Since both natural rewards and addictive drugs induce expression of ΔFosB (i.e., they cause the brain to produce more of it), chronic acquisition of these rewards can result in a similar pathological state of addiction.[106][123] Consequently, ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced sex addictions, which are compulsive sexual behaviors that result from excessive sexual activity and amphetamine use.[106][130][131] These sex addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs.[106][129]

The effects of amphetamine on gene regulation are both dose- and route-dependent.[124] Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.[124] The few studies that have used equivalent (weight-adjusted) human therapeutic doses and oral administration show that these changes, if they occur, are relatively minor.[124] This suggests that medical use of amphetamine does not significantly affect gene regulation.[124]

Dependence and withdrawal

According to another Cochrane Collaboration review on withdrawal in individuals who compulsively use amphetamine and methamphetamine, "when chronic heavy users abruptly discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose."[136] This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in roughly 88% of cases, and persist for 3–4 weeks with a marked "crash" phase occurring during the first week.[136] Amphetamine withdrawal symptoms can include anxiety, drug craving, depressed mood, fatigue, increased appetite, increased movement or decreased movement, lack of motivation, sleeplessness or sleepiness, and lucid dreams.[136] The review indicated that the severity of withdrawal symptoms is positively correlated with the age of the individual and the extent of their dependence.[136] Mild withdrawal symptoms from the discontinuation of amphetamine treatment at therapeutic doses can be avoided by tapering the dose.[2]

Toxicity

In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized by dopamine terminaldegeneration and reduced transporter and receptor function.[137][138] There is no evidence that amphetamine is directly neurotoxic in humans.[139][140] However, large doses of amphetamine may indirectly cause dopaminergic neurotoxicity as a result of hyperpyrexia, the excessive formation of reactive oxygen species, and increased autoxidation of dopamine.[sources 12]Animal models of neurotoxicity from high-dose amphetamine exposure indicate that the occurrence of hyperpyrexia (i.e., core body temperature ≥ 40 °C) is necessary for the development of amphetamine-induced neurotoxicity.[138] Prolonged elevations of brain temperature above 40 °C likely promote the development of amphetamine-induced neurotoxicity in laboratory animals by facilitating the production of reactive oxygen species, disrupting cellular protein function, and transiently increasing blood–brain barrier permeability.[138]

Psychosis

A severe amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as delusions and paranoia.[41] A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about 5–15% of users fail to recover completely.[41][143] According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[41] Psychosis very rarely arises from therapeutic use.[42][85]

In general, there is no significant interaction when consuming amphetamine with food, but the pH of gastrointestinal content and urine affects the absorption and excretion of amphetamine, respectively.[144] Acidic substances reduce the absorption of amphetamine and increase urinary excretion, and alkaline substances do the opposite.[144] Due to the effect pH has on absorption, amphetamine also interacts with gastric acid reducers such as proton pump inhibitors and H2 antihistamines, which increase gastrointestinal pH (i.e., make it less acidic).[144]

Pharmacology

Pharmacodynamics

Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT.[37] Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2.[37][149] When amphetamine enters synaptic vesicles through VMAT2, it collapses the vesicular pH gradient, which in turn causes dopamine to be released into the cytosol (light tan-colored area) through VMAT2.[149][150] When amphetamine binds to TAAR1, it reduces the firing rate of the dopamine neuron via potassium channels and activates protein kinase A (PKA) and protein kinase C (PKC), which subsequently phosphorylate DAT.[37][151][152]PKA-phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport.[37]PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport.[37] Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through a CAMKIIα-dependent pathway, in turn producing dopamine efflux.[153][154]

Amphetamine exerts its behavioral effects by altering the use of monoamines as neuronal signals in the brain, primarily in catecholamine neurons in the reward and executive function pathways of the brain.[37][59] The concentrations of the main neurotransmitters involved in reward circuitry and executive functioning, dopamine and norepinephrine, increase dramatically in a dose-dependent manner by amphetamine due to its effects on monoamine transporters.[37][59][149] The reinforcing and motivational salience-promoting effects of amphetamine are mostly due to enhanced dopaminergic activity in the mesolimbic pathway.[26] The euphoric and locomotor-stimulating effects of amphetamine are dependent upon the magnitude and speed by which it increases synaptic dopamine and norepinephrine concentrations in the striatum.[3]

Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine.[174] Consequently, dextroamphetamine produces greater CNS stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects.[40][174]

Amphetamine is also a substrate for the presynaptic vesicular monoamine transporter, VMAT2.[149][150] Following amphetamine uptake at VMAT2, amphetamine induces the collapse of the vesicular pH gradient, which results in the release of dopamine molecules from synaptic vesicles into the cytosol via dopamine efflux through VMAT2.[149][150] Subsequently, the cytosolic dopamine molecules are released from the presynaptic neuron into the synaptic cleft via reverse transport at DAT.[37][149][150]

Norepinephrine

Similar to dopamine, amphetamine dose-dependently increases the level of synaptic norepinephrine, the direct precursor of epinephrine.[46][59] Based upon neuronal TAAR1mRNA expression, amphetamine is thought to affect norepinephrine analogously to dopamine.[37][149][175] In other words, amphetamine induces TAAR1-mediated efflux and non-competitive reuptake inhibition at phosphorylated NET, competitive NET reuptake inhibition, and norepinephrine release from VMAT2.[37][149]

Pharmacokinetics

The oral bioavailability of amphetamine varies with gastrointestinal pH;[144] it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine.[9] Amphetamine is a weak base with a pKa of 9.9;[4] consequently, when the pH is basic, more of the drug is in its lipid soluble free base form, and more is absorbed through the lipid-rich cell membranes of the gut epithelium.[4][144] Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed.[4] Approximately 15–40% of amphetamine circulating in the bloodstream is bound to plasma proteins.[10] Following absorption, amphetamine readily distributes into most tissues in the body, with high concentrations occurring in cerebrospinal fluid and brain tissue.[16]

The half-life of amphetamine enantiomers differ and vary with urine pH.[4] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.[4] Highly acidic urine will reduce the enantiomer half-lives to 7 hours;[16] highly alkaline urine will increase the half-lives up to 34 hours.[16] The immediate-release and extended release variants of salts of both isomers reach peak plasma concentrations at 3 hours and 7 hours post-dose respectively.[4] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[4] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.[4] When urine pH is abnormal, the urinary recovery of amphetamine may range from a low of 1% to a high of 75%, depending mostly upon whether urine is too basic or acidic, respectively.[4] Following oral administration, amphetamine appears in urine within 3 hours.[16] Roughly 90% of ingested amphetamine is eliminated 3 days after the last oral dose.[16]

The prodrug lisdexamfetamine is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract;[177] following absorption into the blood stream, it is converted by red blood cell-associated enzymes to dextroamphetamine via hydrolysis.[177] The elimination half-life of lisdexamfetamine is generally less than 1 hour.[177]

The primary active metabolites of amphetamine are 4-hydroxyamphetamine and norephedrine;[11] at normal urine pH, about 30–40% of amphetamine is excreted unchanged and roughly 50% is excreted as the inactive metabolites (bottom row).[4] The remaining 10–20% is excreted as the active metabolites.[4] Benzoic acid is metabolized by XM-ligase into an intermediate product, benzoyl-CoA, which is then metabolized by GLYAT into hippuric acid.[183]

Synthesis

Since the first preparation was reported in 1887,[194] numerous synthetic routes to amphetamine have been developed.[195][196] The most common route of both legal and illicit amphetamine synthesis employs a non-metal reduction known as the Leuckart reaction (method 1).[47][197] In the first step, a reaction between phenylacetone and formamide, either using additional formic acid or formamide itself as a reducing agent, yields N-formylamphetamine. This intermediate is then hydrolyzed using hydrochloric acid, and subsequently basified, extracted with organic solvent, concentrated, and distilled to yield the free base. The free base is then dissolved in an organic solvent, sulfuric acid added, and amphetamine precipitates out as the sulfate salt.[197][198]

A number of chiral resolutions have been developed to separate the two enantiomers of amphetamine.[195] For example, racemic amphetamine can be treated with d-tartaric acid to form a diastereoisomeric salt which is fractionally crystallized to yield dextroamphetamine.[199] Chiral resolution remains the most economical method for obtaining optically pure amphetamine on a large scale.[200] In addition, several enantioselective syntheses of amphetamine have been developed. In one example, optically pure(R)-1-phenyl-ethanamine is condensed with phenylacetone to yield a chiral Schiff base. In the key step, this intermediate is reduced by catalytic hydrogenation with a transfer of chirality to the carbon atom alpha to the amino group. Cleavage of the benzylic amine bond by hydrogenation yields optically pure dextroamphetamine.[200]

Amphetamine is still illegally synthesized today in clandestine labs and sold on the black market, primarily in European countries.[226] Among European Union (EU) member states, 1.2 million young adults used illicit amphetamine or methamphetamine in 2013.[227] During 2012, approximately 5.9 metric tons of illicit amphetamine were seized within EU member states;[227] the "street price" of illicit amphetamine within the EU ranged from €6–38 per gram during the same period.[227] Outside Europe, the illicit market for amphetamine is much smaller than the market for methamphetamine and MDMA.[226]

Pharmaceutical products

Several currently prescribed amphetamine formulations contain both enantiomers, including Adderall, Adderall XR, Mydayis, Adzenys XR-ODT, Dyanavel XR, and Evekeo, the last of which contains racemic amphetamine sulfate.[2][35][90] Amphetamine is also prescribed in enantiopure and prodrug form as dextroamphetamine and lisdexamfetamine respectively.[36][177] Lisdexamfetamine is structurally different from amphetamine, and is inactive until it metabolizes into dextroamphetamine.[177] The free base of racemic amphetamine was previously available as Benzedrine, Psychedrine, and Sympatedrine.[3] Levoamphetamine was previously available as Cydril.[3] Many current amphetamine pharmaceuticals are salts due to the comparatively high volatility of the free base.[3][36][47] However, oral suspension and orally disintegrating tablet (ODT) dosage forms composed of the free base were introduced in 2015 and 2016, respectively.[90][237][238] Some of the current brands and their generic equivalents are listed below.

^Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.[25]Levoamphetamine and dextroamphetamine are also known as L-amph or levamfetamine (INN) and D-amph or dexamfetamine (INN) respectively.[18]

^"Adderall" is a brand name as opposed to a nonproprietary name; because the latter ("dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate, and amphetamine aspartate"[36]) is excessively long, this article exclusively refers to this amphetamine mixture by the brand name.

^The term "amphetamines" also refers to a chemical class, but, unlike the class of substituted amphetamines,[5] the "amphetamines" class does not have a standardized definition in academic literature.[19] One of the more restrictive definitions of this class includes only the racemate and enantiomers of amphetamine and methamphetamine.[19] The most general definition of the class encompasses a broad range of pharmacologically and structurally related compounds.[19]Due to confusion that may arise from use of the plural form, this article will only use the terms "amphetamine" and "amphetamines" to refer to racemic amphetamine, levoamphetamine, and dextroamphetamine and reserve the term "substituted amphetamines" for its structural class.

The largest effect sizes for outcome improvements from long-term stimulant therapy occur in the domains involving academics (e.g., grade point average, achievement test scores, length of education, and education level), self-esteem (e.g., self-esteem questionnaire assessments, number of suicide attempts, and suicide rates), and social function (e.g., peer nomination scores, social skills, and quality of peer, family, and romantic relationships).[56]

Long-term combination therapy for ADHD (i.e., treatment with both a stimulant and behavioral therapy) produces even larger effect sizes for outcome improvements and improves a larger proportion of outcomes across each domain compared to long-term stimulant therapy alone.[56]

^The statements supported by the USFDA come from prescribing information, which is the copyrighted intellectual property of the manufacturer and approved by the USFDA. USFDA contraindications are not necessarily intended to limit medical practice but limit claims by pharmaceutical companies.[84]

^According to one review, amphetamine can be prescribed to individuals with a history of abuse provided that appropriate medication controls are employed, such as requiring daily pick-ups of the medication from the prescribing physician.[3]

^In individuals who experience sub-normal height and weight gains, a rebound to normal levels is expected to occur if stimulant therapy is briefly interrupted.[55][57][89] The average reduction in final adult height from 3 years of continuous stimulant therapy is 2 cm.[89]

^The 95% confidence interval indicates that there is a 95% probability that the true number of deaths lies between 3,425 and 4,145.

^Transcription factors are proteins that increase or decrease the expression of specific genes.[125]

^In simpler terms, this necessary and sufficient relationship means that ΔFosB overexpression in the nucleus accumbens and addiction-related behavioral and neural adaptations always occur together and never occur alone.

^4-Hydroxyamphetamine has been shown to be metabolized into 4-hydroxynorephedrine by dopamine beta-hydroxylase (DBH) in vitro and it is presumed to be metabolized similarly in vivo.[5][182] Evidence from studies that measured the effect of serum DBH concentrations on 4-hydroxyamphetamine metabolism in humans suggests that a different enzyme may mediate the conversion of 4-hydroxyamphetamine to 4-hydroxynorephedrine;[182][184] however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain.[185][186]

^Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.[25]

^The active ingredient in some OTC inhalers in the United States is listed as levmetamfetamine, the INN and USAN of levomethamphetamine.[211][212]

^For uniformity, molecular masses were calculated using the Lenntech Molecular Weight Calculator[242] and were within 0.01g/mol of published pharmaceutical values.

^This product (Dyanavel XR) is an oral suspension (i.e., a drug that is suspended in a liquid and taken by mouth) that contains 2.5 mg/mL of amphetamine base.[90] The product uses an ion exchange resin to achieve extended release of the amphetamine base.[90]

^ abcdefghijklmHeal DJ, Smith SL, Gosden J, Nutt DJ (June 2013). "Amphetamine, past and present – a pharmacological and clinical perspective". J. Psychopharmacol. 27 (6): 479–496. doi:10.1177/0269881113482532. PMC3666194. PMID23539642. The intravenous use of d-amphetamine and other stimulants still pose major safety risks to the individuals indulging in this practice. Some of this intravenous abuse is derived from the diversion of ampoules of d-amphetamine, which are still occasionally prescribed in the UK for the control of severe narcolepsy and other disorders of excessive sedation. ... For these reasons, observations of dependence and abuse of prescription d-amphetamine are rare in clinical practice, and this stimulant can even be prescribed to people with a history of drug abuse provided certain controls, such as daily pick-ups of prescriptions, are put in place (Jasinski and Krishnan, 2009b).

^ abcdef"Metabolism/Pharmacokinetics". Amphetamine. United States National Library of Medicine – Toxicology Data Network. Hazardous Substances Data Bank. Archived from the original on 2 October 2017. Retrieved 2 October 2017. Duration of effect varies depending on agent and urine pH. Excretion is enhanced in more acidic urine. Half-life is 7 to 34 hours and is, in part, dependent on urine pH (half-life is longer with alkaline urine). ... Amphetamines are distributed into most body tissues with high concentrations occurring in the brain and CSF. Amphetamine appears in the urine within about 3 hours following oral administration. ... Three days after a dose of (+ or -)-amphetamine, human subjects had excreted 91% of the (14)C in the urine

^ abcd"Compound Summary". Amphetamine. PubChem Compound. United States National Library of Medicine – National Center for Biotechnology Information. 11 April 2015. Retrieved 17 April 2015.

^ abcdeYoshida T (1997). "Chapter 1: Use and Misuse of Amphetamines: An International Overview". In Klee H. Amphetamine Misuse: International Perspectives on Current Trends. Amsterdam, Netherlands: Harwood Academic Publishers. p. 2. ISBN9789057020810. Retrieved 1 December 2014. Amphetamine, in the singular form, properly applies to the racemate of 2-amino-1-phenylpropane. ... In its broadest context, however, the term [amphetamines] can even embrace a large number of structurally and pharmacologically related substances.

^"Density". Amphetamine. PubChem Compound. United States National Library of Medicine – National Center for Biotechnology Information. 5 November 2016. Retrieved 9 November 2016.

^ ab"Enantiomer". IUPAC Goldbook. International Union of Pure and Applied Chemistry. doi:10.1351/goldbook.E02069. Archived from the original on 17 March 2013. Retrieved 14 March 2014. One of a pair of molecular entities which are mirror images of each other and non-superposable.

^ abcdefghijMalenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. pp. 318, 321. ISBN9780071481274. Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in normal subjects and those with ADHD. ... stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks ... through indirect stimulation of dopamine and norepinephrine receptors. ...Beyond these general permissive effects, dopamine (acting via D1 receptors) and norepinephrine (acting at several receptors) can, at optimal levels, enhance working memory and aspects of attention.

^ abcdRasmussen N (July 2006). "Making the first anti-depressant: amphetamine in American medicine, 1929–1950". J. Hist. Med. Allied Sci. 61 (3): 288–323. doi:10.1093/jhmas/jrj039. PMID16492800. However the firm happened to discover the drug, SKF first packaged it as an inhaler so as to exploit the base’s volatility and, after sponsoring some trials by East Coast otolaryngological specialists, began to advertise the Benzedrine Inhaler as a decongestant in late 1933.

^"Amphetamine". Medical Subject Headings. United States National Library of Medicine. Retrieved 16 December 2013.

^"Guidelines on the Use of International Nonproprietary Names (INNS) for Pharmaceutical Substances". World Health Organization. 1997. Retrieved 1 December 2014. In principle, INNs are selected only for the active part of the molecule which is usually the base, acid or alcohol. In some cases, however, the active molecules need to be expanded for various reasons, such as formulation purposes, bioavailability or absorption rate. In 1975 the experts designated for the selection of INN decided to adopt a new policy for naming such molecules. In future, names for different salts or esters of the same active substance should differ only with regard to the inactive moiety of the molecule. ... The latter are called modified INNs (INNMs).

^ abcdeShoptaw SJ, Kao U, Ling W (January 2009). Shoptaw SJ, Ali R, ed. "Treatment for amphetamine psychosis". Cochrane Database Syst. Rev. (1): CD003026. doi:10.1002/14651858.CD003026.pub3. PMID19160215. A minority of individuals who use amphetamines develop full-blown psychosis requiring care at emergency departments or psychiatric hospitals. In such cases, symptoms of amphetamine psychosis commonly include paranoid and persecutory delusions as well as auditory and visual hallucinations in the presence of extreme agitation. More common (about 18%) is for frequent amphetamine users to report psychotic symptoms that are sub-clinical and that do not require high-intensity intervention ...About 5–15% of the users who develop an amphetamine psychosis fail to recover completely (Hofmann 1983) ...Findings from one trial indicate use of antipsychotic medications effectively resolves symptoms of acute amphetamine psychosis.

^ abMalenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 16: Reinforcement and Addictive Disorders". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). New York: McGraw-Hill Medical. ISBN9780071827706. Such agents also have important therapeutic uses; cocaine, for example, is used as a local anesthetic (Chapter 2), and amphetamines and methylphenidate are used in low doses to treat attention deficit hyperactivity disorder and in higher doses to treat narcolepsy (Chapter 12). Despite their clinical uses, these drugs are strongly reinforcing, and their long-term use at high doses is linked with potential addiction, especially when they are rapidly administered or when high-potency forms are given.

^ abKollins SH (May 2008). "A qualitative review of issues arising in the use of psycho-stimulant medications in patients with ADHD and co-morbid substance use disorders". Curr. Med. Res. Opin. 24 (5): 1345–1357. doi:10.1185/030079908X280707. PMID18384709. When oral formulations of psychostimulants are used at recommended doses and frequencies, they are unlikely to yield effects consistent with abuse potential in patients with ADHD.

^ abFrodl T, Skokauskas N (February 2012). "Meta-analysis of structural MRI studies in children and adults with attention deficit hyperactivity disorder indicates treatment effects". Acta psychiatrica Scand. 125 (2): 114–126. doi:10.1111/j.1600-0447.2011.01786.x. PMID22118249. Basal ganglia regions like the right globus pallidus, the right putamen, and the nucleus caudatus are structurally affected in children with ADHD. These changes and alterations in limbic regions like ACC and amygdala are more pronounced in non-treated populations and seem to diminish over time from child to adulthood. Treatment seems to have positive effects on brain structure.

^ abcdMillichap JG (2010). "Chapter 9: Medications for ADHD". In Millichap JG. Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD (2nd ed.). New York, USA: Springer. pp. 121–123, 125–127. ISBN9781441913968. Ongoing research has provided answers to many of the parents’ concerns, and has confirmed the effectiveness and safety of the long-term use of medication.

^ abcdeHuang YS, Tsai MH (July 2011). "Long-term outcomes with medications for attention-deficit hyperactivity disorder: current status of knowledge". CNS Drugs. 25 (7): 539–554. doi:10.2165/11589380-000000000-00000. PMID21699268. Recent studies have demonstrated that stimulants, along with the non-stimulants atomoxetine and extended-release guanfacine, are continuously effective for more than 2-year treatment periods with few and tolerable adverse effects. The effectiveness of long-term therapy includes not only the core symptoms of ADHD, but also improved quality of life and academic achievements. The most concerning short-term adverse effects of stimulants, such as elevated blood pressure and heart rate, waned in long-term follow-up studies. ... In the longest follow-up study (of more than 10 years), lifetime stimulant treatment for ADHD was effective and protective against the development of adverse psychiatric disorders.

^ abSpencer RC, Devilbiss DM, Berridge CW (June 2015). "The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex". Biol. Psychiatry. 77 (11): 940–950. doi:10.1016/j.biopsych.2014.09.013. PMC4377121. PMID25499957. The procognitive actions of psychostimulants are only associated with low doses. Surprisingly, despite nearly 80 years of clinical use, the neurobiology of the procognitive actions of psychostimulants has only recently been systematically investigated. Findings from this research unambiguously demonstrate that the cognition-enhancing effects of psychostimulants involve the preferential elevation of catecholamines in the PFC and the subsequent activation of norepinephrine α2 and dopamine D1 receptors. ... This differential modulation of PFC-dependent processes across dose appears to be associated with the differential involvement of noradrenergic α2 versus α1 receptors. Collectively, this evidence indicates that at low, clinically relevant doses, psychostimulants are devoid of the behavioral and neurochemical actions that define this class of drugs and instead act largely as cognitive enhancers (improving PFC-dependent function). ... In particular, in both animals and humans, lower doses maximally improve performance in tests of working memory and response inhibition, whereas maximal suppression of overt behavior and facilitation of attentional processes occurs at higher doses.

^Ilieva IP, Hook CJ, Farah MJ (June 2015). "Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis". J. Cogn. Neurosci. 27 (6): 1–21. doi:10.1162/jocn_a_00776. PMID25591060. Specifically, in a set of experiments limited to high-quality designs, we found significant enhancement of several cognitive abilities. ... The results of this meta-analysis ... do confirm the reality of cognitive enhancing effects for normal healthy adults in general, while also indicating that these effects are modest in size.

^Clemow DB, Walker DJ (September 2014). "The potential for misuse and abuse of medications in ADHD: a review". Postgrad. Med. 126 (5): 64–81. doi:10.3810/pgm.2014.09.2801. PMID25295651. Overall, the data suggest that ADHD medication misuse and diversion are common health care problems for stimulant medications, with the prevalence believed to be approximately 5% to 10% of high school students and 5% to 35% of college students, depending on the study.

^ abcdParr JW (July 2011). "Attention-deficit hyperactivity disorder and the athlete: new advances and understanding". Clin. Sports Med. 30 (3): 591–610. doi:10.1016/j.csm.2011.03.007. PMID21658550. In 1980, Chandler and Blair47 showed significant increases in knee extension strength, acceleration, anaerobic capacity, time to exhaustion during exercise, pre-exercise and maximum heart rates, and time to exhaustion during maximal oxygen consumption (VO2 max) testing after administration of 15 mg of dextroamphetamine versus placebo. Most of the information to answer this question has been obtained in the past decade through studies of fatigue rather than an attempt to systematically investigate the effect of ADHD drugs on exercise.

^ abcRoelands B, de Koning J, Foster C, Hettinga F, Meeusen R (May 2013). "Neurophysiological determinants of theoretical concepts and mechanisms involved in pacing". Sports Med. 43 (5): 301–311. doi:10.1007/s40279-013-0030-4. PMID23456493. In high-ambient temperatures, dopaminergic manipulations clearly improve performance. The distribution of the power output reveals that after dopamine reuptake inhibition, subjects are able to maintain a higher power output compared with placebo. ... Dopaminergic drugs appear to override a safety switch and allow athletes to use a reserve capacity that is ‘off-limits’ in a normal (placebo) situation.

^Roelands B, De Pauw K, Meeusen R (June 2015). "Neurophysiological effects of exercise in the heat". Scand. J. Med. Sci. Sports. 25 Suppl 1: 65–78. doi:10.1111/sms.12350. PMID25943657. This indicates that subjects did not feel they were producing more power and consequently more heat. The authors concluded that the “safety switch” or the mechanisms existing in the body to prevent harmful effects are overridden by the drug administration (Roelands et al., 2008b). Taken together, these data indicate strong ergogenic effects of an increased DA concentration in the brain, without any change in the perception of effort.

^Kessler S (January 1996). "Drug therapy in attention-deficit hyperactivity disorder". South. Med. J. 89 (1): 33–38. doi:10.1097/00007611-199601000-00005. PMID8545689. statements on package inserts are not intended to limit medical practice. Rather they are intended to limit claims by pharmaceutical companies. ... the FDA asserts explicitly, and the courts have upheld that clinical decisions are to be made by physicians and patients in individual situations.

^ abcdeNestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues Clin. Neurosci. 15 (4): 431–443. PMC3898681. PMID24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41. ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.

^ abcdefghijklmnopqrstuvOlsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–1122. doi:10.1016/j.neuropharm.2011.03.010. PMC3139704. PMID21459101. Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader, 2008).

^ abcdLynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA (September 2013). "Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis". Neurosci. Biobehav. Rev. 37 (8): 1622–1644. doi:10.1016/j.neubiorev.2013.06.011. PMC3788047. PMID23806439. These findings suggest that exercise may “magnitude”-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuroadaptive changes that develop during and following extended access to the drug. ... Exercise has been proposed as a treatment for drug addiction that may reduce drug craving and risk of relapse. Although few clinical studies have investigated the efficacy of exercise for preventing relapse, the few studies that have been conducted generally report a reduction in drug craving and better treatment outcomes ... Taken together, these data suggest that the potential benefits of exercise during relapse, particularly for relapse to psychostimulants, may be mediated via chromatin remodeling and possibly lead to greater treatment outcomes.

^"Glossary of Terms". Mount Sinai School of Medicine. Department of Neuroscience. Retrieved 9 February 2015.

^Volkow ND, Koob GF, McLellan AT (January 2016). "Neurobiologic Advances from the Brain Disease Model of Addiction". N. Engl. J. Med. 374 (4): 363–371. doi:10.1056/NEJMra1511480. PMID26816013. Substance-use disorder: A diagnostic term in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other drugs that causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home. Depending on the level of severity, this disorder is classified as mild, moderate, or severe.Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder.

^ abcRenthal W, Nestler EJ (September 2009). "Chromatin regulation in drug addiction and depression". Dialogues Clin. Neurosci. 11 (3): 257–268. PMC2834246. PMID19877494. [Psychostimulants] increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein (CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes including fosB and c-fos in response to psychostimulant exposure. ΔFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg, c-fos) where it recruits HDAC1 as a corepressor. ... Chronic exposure to psychostimulants increases glutamatergic [signaling] from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5.Figure 2: Psychostimulant-induced signaling events

^Broussard JI (January 2012). "Co-transmission of dopamine and glutamate". J. Gen. Physiol. 139 (1): 93–96. doi:10.1085/jgp.201110659. PMC3250102. PMID22200950. Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.

^ abcNestler EJ (December 2012). "Transcriptional mechanisms of drug addiction". Clin. Psychopharmacol. Neurosci. 10 (3): 136–143. doi:10.9758/cpn.2012.10.3.136. PMC3569166. PMID23430970. The 35-37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. ... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. ... ΔFosB overexpression in nucleus accumbens induces NFκB ... In contrast, the ability of ΔFosB to repress the c-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase

^ abPerez-Mana C, Castells X, Torrens M, Capella D, Farre M (September 2013). "Efficacy of psychostimulant drugs for amphetamine abuse or dependence". Cochrane Database Syst. Rev. 9 (9): CD009695. doi:10.1002/14651858.CD009695.pub2. PMID23996457. To date, no pharmacological treatment has been approved for [addiction], and psychotherapy remains the mainstay of treatment. ... Results of this review do not support the use of psychostimulant medications at the tested doses as a replacement therapy

^ abcCarroll ME, Smethells JR (February 2016). "Sex Differences in Behavioral Dyscontrol: Role in Drug Addiction and Novel Treatments". Front. Psychiatry. 6: 175. doi:10.3389/fpsyt.2015.00175. PMC4745113. PMID26903885. Physical ExerciseThere is accelerating evidence that physical exercise is a useful treatment for preventing and reducing drug addiction ... In some individuals, exercise has its own rewarding effects, and a behavioral economic interaction may occur, such that physical and social rewards of exercise can substitute for the rewarding effects of drug abuse. ... The value of this form of treatment for drug addiction in laboratory animals and humans is that exercise, if it can substitute for the rewarding effects of drugs, could be self-maintained over an extended period of time. Work to date in [laboratory animals and humans] regarding exercise as a treatment for drug addiction supports this hypothesis. ... Animal and human research on physical exercise as a treatment for stimulant addiction indicates that this is one of the most promising treatments on the horizon.

^ abcdBowyer JF, Hanig JP (November 2014). "Amphetamine- and methamphetamine-induced hyperthermia: Implications of the effects produced in brain vasculature and peripheral organs to forebrain neurotoxicity". Temperature (Austin). 1 (3): 172–182. doi:10.4161/23328940.2014.982049. PMC5008711. PMID27626044. Hyperthermia alone does not produce amphetamine-like neurotoxicity but AMPH and METH exposures that do not produce hyperthermia (≥40°C) are minimally neurotoxic. Hyperthermia likely enhances AMPH and METH neurotoxicity directly through disruption of protein function, ion channels and enhanced ROS production. ... The hyperthermia and the hypertension produced by high doses amphetamines are a primary cause of transient breakdowns in the blood-brain barrier (BBB) resulting in concomitant regional neurodegeneration and neuroinflammation in laboratory animals. ... In animal models that evaluate the neurotoxicity of AMPH and METH, it is quite clear that hyperthermia is one of the essential components necessary for the production of histological signs of dopamine terminal damage and neurodegeneration in cortex, striatum, thalamus and hippocampus.

^"Amphetamine". United States National Library of Medicine – Toxicology Data Network. Hazardous Substances Data Bank. Archived from the original on 2 October 2017. Retrieved 2 October 2017. Direct toxic damage to vessels seems unlikely because of the dilution that occurs before the drug reaches the cerebral circulation.

^Krause J (April 2008). "SPECT and PET of the dopamine transporter in attention-deficit/hyperactivity disorder". Expert Rev. Neurother. 8 (4): 611–625. doi:10.1586/14737175.8.4.611. PMID18416663. Zinc binds at ... extracellular sites of the DAT [103], serving as a DAT inhibitor. In this context, controlled double-blind studies in children are of interest, which showed positive effects of zinc [supplementation] on symptoms of ADHD [105,106]. It should be stated that at this time [supplementation] with zinc is not integrated in any ADHD treatment algorithm.

^ abcdSulzer D, Cragg SJ, Rice ME (August 2016). "Striatal dopamine neurotransmission: regulation of release and uptake". Basal Ganglia. 6 (3): 123–148. doi:10.1016/j.baga.2016.02.001. PMC4850498. PMID27141430. Despite the challenges in determining synaptic vesicle pH, the proton gradient across the vesicle membrane is of fundamental importance for its function. Exposure of isolated catecholamine vesicles to protonophores collapses the pH gradient and rapidly redistributes transmitter from inside to outside the vesicle. ... Amphetamine and its derivatives like methamphetamine are weak base compounds that are the only widely used class of drugs known to elicit transmitter release by a non-exocytic mechanism. As substrates for both DAT and VMAT, amphetamines can be taken up to the cytosol and then sequestered in vesicles, where they act to collapse the vesicular pH gradient.

^ abcVicentic A, Jones DC (February 2007). "The CART (cocaine- and amphetamine-regulated transcript) system in appetite and drug addiction". J. Pharmacol. Exp. Ther. 320 (2): 499–506. doi:10.1124/jpet.105.091512. PMID16840648. The physiological importance of CART was further substantiated in numerous human studies demonstrating a role of CART in both feeding and psychostimulant addiction. ... Colocalization studies also support a role for CART in the actions of psychostimulants. ... CART and DA receptor transcripts colocalize (Beaudry et al., 2004). Second, dopaminergic nerve terminals in the NAc synapse on CART-containing neurons (Koylu et al., 1999), hence providing the proximity required for neurotransmitter signaling. These studies suggest that DA plays a role in regulating CART gene expression possibly via the activation of CREB.

^Zhang M, Han L, Xu Y (June 2012). "Roles of cocaine- and amphetamine-regulated transcript in the central nervous system". Clin. Exp. Pharmacol. Physiol. 39 (6): 586–592. doi:10.1111/j.1440-1681.2011.05642.x. PMID22077697. Recently, it was demonstrated that CART, as a neurotrophic peptide, had a cerebroprotective against focal ischaemic stroke and inhibited the neurotoxicity of β-amyloid protein, which focused attention on the role of CART in the central nervous system (CNS) and neurological diseases. ... The literature indicates that there are many factors, such as regulation of the immunological system and protection against energy failure, that may be involved in the cerebroprotection afforded by CART

^"Compound Summary". p-Hydroxyamphetamine. PubChem Compound. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 15 October 2013.

^"Compound Summary". p-Hydroxynorephedrine. PubChem Compound. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 15 October 2013.

^"Compound Summary". Phenylpropanolamine. PubChem Compound. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 15 October 2013.

^"Pharmacology and Biochemistry". Amphetamine. Pubchem Compound. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 12 October 2013.

^ abcSjoerdsma A, von Studnitz W (April 1963). "Dopamine-beta-oxidase activity in man, using hydroxyamphetamine as substrate". Br. J. Pharmacol. Chemother. 20: 278–284. doi:10.1111/j.1476-5381.1963.tb01467.x. PMC1703637. PMID13977820. Hydroxyamphetamine was administered orally to five human subjects ... Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by the action of dopamine-β-oxidase, a simple method is suggested for measuring the activity of this enzyme and the effect of its inhibitors in man. ... The lack of effect of administration of neomycin to one patient indicates that the hydroxylation occurs in body tissues. ... a major portion of the β-hydroxylation of hydroxyamphetamine occurs in non-adrenal tissue. Unfortunately, at the present time one cannot be completely certain that the hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts dopamine to noradrenaline.

^ abBadenhorst CP, van der Sluis R, Erasmus E, van Dijk AA (September 2013). "Glycine conjugation: importance in metabolism, the role of glycine N-acyltransferase, and factors that influence interindividual variation". Expert Opin. Drug Metab. Toxicol. 9 (9): 1139–1153. doi:10.1517/17425255.2013.796929. PMID23650932. Figure 1. Glycine conjugation of benzoic acid. The glycine conjugation pathway consists of two steps. First benzoate is ligated to CoASH to form the high-energy benzoyl-CoA thioester. This reaction is catalyzed by the HXM-A and HXM-B medium-chain acid:CoA ligases and requires energy in the form of ATP. ... The benzoyl-CoA is then conjugated to glycine by GLYAT to form hippuric acid, releasing CoASH. In addition to the factors listed in the boxes, the levels of ATP, CoASH, and glycine may influence the overall rate of the glycine conjugation pathway.

^Horwitz D, Alexander RW, Lovenberg W, Keiser HR (May 1973). "Human serum dopamine-β-hydroxylase. Relationship to hypertension and sympathetic activity". Circ. Res. 32 (5): 594–599. doi:10.1161/01.RES.32.5.594. PMID4713201. The biologic significance of the different levels of serum DβH activity was studied in two ways. First, in vivo ability to β-hydroxylate the synthetic substrate hydroxyamphetamine was compared in two subjects with low serum DβH activity and two subjects with average activity. ... In one study, hydroxyamphetamine (Paredrine), a synthetic substrate for DβH, was administered to subjects with either low or average levels of serum DβH activity. The percent of the drug hydroxylated to hydroxynorephedrine was comparable in all subjects (6.5-9.62) (Table 3).

^Freeman JJ, Sulser F (December 1974). "Formation of p-hydroxynorephedrine in brain following intraventricular administration of p-hydroxyamphetamine". Neuropharmacology. 13 (12): 1187–1190. doi:10.1016/0028-3908(74)90069-0. PMID4457764. In species where aromatic hydroxylation of amphetamine is the major metabolic pathway, p-hydroxyamphetamine (POH) and p-hydroxynorephedrine (PHN) may contribute to the pharmacological profile of the parent drug. ... The location of the p-hydroxylation and β-hydroxylation reactions is important in species where aromatic hydroxylation of amphetamine is the predominant pathway of metabolism. Following systemic administration of amphetamine to rats, POH has been found in urine and in plasma.The observed lack of a significant accumulation of PHN in brain following the intraventricular administration of (+)-amphetamine and the formation of appreciable amounts of PHN from (+)-POH in brain tissue in vivo supports the view that the aromatic hydroxylation of amphetamine following its systemic administration occurs predominantly in the periphery, and that POH is then transported through the blood-brain barrier, taken up by noradrenergic neurones in brain where (+)-POH is converted in the storage vesicles by dopamine β-hydroxylase to PHN.

^ ab"Clinical Drug Testing in Primary Care"(PDF). University of Colorado Denver. Technical Assistance Publication Series 32. United States Department of Health and Human Services – Substance Abuse and Mental Health Services Administration. 2012. p. 55. Archived(PDF) from the original on 14 May 2018. Retrieved 31 October 2013. A single dose of amphetamine or methamphetamine can be detected in the urine for approximately 24 hours, depending upon urine pH and individual metabolic differences. People who use chronically and at high doses may continue to have positive urine specimens for 2–4 days after last use (SAMHSA, 2010b).

1.
Levoamphetamine
–
Pharmaceuticals that contain levoamphetamine are currently indicated and prescribed for the treatment of attention deficit hyperactivity disorder, obesity, and narcolepsy in some countries. Levoamphetamine is the stereoisomer of the amphetamine molecule. Levoamphetamine is the stereoisomer of the amphetamine molecule. Racemic amphetamine contains two optical isomers, dextroamphetamine and levoamphetamine and it was later realized that the amphetamine enantiomers could treat obesity, narcolepsy, and ADHD. Because of the central nervous system effect of the dextro enantiomer, sold as Dexedrine. However, in 2012 racemic amphetamine sulfate was reintroduced as the Evekeo brandname, adderall is an amphetamine pharmaceutical that contains 25% levoamphetamine salts. Evekeo is an amphetamine medication FDA approved as therapeutic equivalent that contains 50% levoamphetamine sulfate and it is approved for narcolepsy, ADHD and exogenous obesity. Products using amphetamine base are now marketed, dyanevel XR, a liquid suspension form became available in 2015, and contains about 24% levoamphetamine. Adzenys XR, an orally dissolving tablet came to market in 2016, l-Amphetamine succinate was sold in Hungary between 1952 and 1955 under the brand name Cydril

2.
Drug nomenclature
–
Drug nomenclature is the systematic naming of drugs, especially pharmaceutical drugs. Generic names for drugs are nowadays constructed out of affixes and stems that classify the drugs into different categories, a marketed drug might also have a company code or compound code. The chemical names are the names, based on the molecular structure of the drug. There are various systems of nomenclature and thus various chemical names for any one substance. The most important is the IUPAC name, chemical names are typically very long and too complex to be commonly used in referring to a drug. Sometimes, a company that is developing a drug might give the drug a company code, for example, CDP870 is UCB’s company code for Cimzia. Many of these codes, although not all, have prefixes that correspond to the company name, during development, the company will apply for regulatory approval of the drug by the relevant national regulatory agency, and it will apply for a generic name for that country. It will also apply for an International Nonproprietary Name through the World Health Organization, nowadays the national nonproprietary names are usually the same as the INN. The generic names usually indicate via their stems what drug class the drug belongs to, for example, one can tell that aciclovir is an antiviral drug because its name ends in the -vir suffix. Otherwise the 2 names are both given, joined by hyphens or slashes. For example, suspensions combining trimethoprim and sulfamethoxazole are called either trimethoprim/sulfamethoxazole or co-trimoxazole, similarly, co-codamol is codeine-acetaminophen, and co-triamterzide is triamterene-hydrochlorothiazide. The USP ceased maintaining PENs, but the similar co-prefixed BANs are still current, for drugs that make it all the way through development, testing, and regulatory acceptance, the pharmaceutical company then gives the drug a trade name. The term trade name is a term in the pharmaceutical industry for a brand name or trademark name. For example, Lipitor is Pfizers trade name for atorvastatin, a cholesterol-lowering medication, Drug names are often subject to legal regulation, including approval for new drugs and on packaging to establish clear rules about adulterants and fraudulent or misleading labelling. A national formulary is often designated to define drug names for regulatory purposes, unbiased mentions of a drug place the nonproprietary name first and follow it with the trade name in parentheses, if relevant. This pattern is important for the literature, where conflict of interest is disclosed or avoided. The authors reporting on a study are not endorsing any particular brand of drug and they will often state which brand was used, for methodologic validity, but they do so in a way that makes clear the absence of endorsement. For example, the 2015 American Society of Hematology publication policies say, Non-proprietary names should be used and he first letter of the name of a proprietary drug should be capitalized

3.
Drugs.com
–
Drugs. com is an online pharmaceutical encyclopedia which provides drug information for consumers and healthcare professionals primarily in the USA. The domain Drugs. com was registered by Bonnie Neubeck in 1994. In 1999 at the height of the boom, Eric MacIver purchased an option to buy the domain from Neubeck. com. Venture Frogs sold the drugs. com domain name to an investor in June 2001. The Drugs. com website is owned and operated by the Drugsite Trust, the Drugsite Trust is a privately held Trust administered by two New Zealand pharmacists, Karen Ann and Phillip James Thornton The Drugs. com website was officially launched in September 2001. Stedmans, AHFS, Harvard Health Publications, Mayoclinic, North American Compendiums, in March 2008, Drugs. com announced the release of Mednotes —an online personal medication record application which connected to Google Health. In May 2010, U. S. FDA announced a collaboration with Drugs. com to distribute consumer health updates on the Drugs. com website, Drugs. com is certified by the TRUSTe online privacy certification program and the HONcode Health on the Net Foundation

4.
Addiction
–
Addiction is a brain disorder characterized by compulsive engagement in rewarding stimuli, despite adverse consequences. The two properties that characterize all addictive stimuli are that they are reinforcing and intrinsically rewarding, ΔFosB, a gene transcription factor, is a critical component and common factor in the development of virtually all forms of behavioral and drug addictions. Due to the relationship between ΔFosB expression and addictions, it is used preclinically as an addiction biomarker. ΔFosB expression in these neurons directly and positively regulates drug self-administration and reward sensitization through positive reinforcement, classic hallmarks of addiction include impaired control over substances or behavior, preoccupation with substance or behavior, and continued use despite consequences. Habits and patterns associated with addiction are typically characterized by immediate gratification, the only behavioral addiction recognized by the DSM-5 is gambling addiction. The term addiction is misused frequently to refer to other behaviors or disorders, particularly dependence. Addiction is the use of a substance or performance of a behavior that is independent of withdrawal. Cognitive control and stimulus control, which is associated with operant and classical conditioning, cognitive control, and particularly inhibitory control over behavior, is impaired in both addiction and attention deficit hyperactivity disorder. Stimulus-driven behavioral responses that are associated with a rewarding stimulus tend to dominate ones behavior in an addiction. The term behavioral addiction correctly refers to a compulsion to engage in a natural reward – which is a behavior that is inherently rewarding – despite adverse consequences, reviews of preclinical studies indicate that long-term frequent and excessive consumption of high fat or sugar foods can produce an addiction. Gambling is a natural reward which is associated with behavior and for which clinical diagnostic manuals. There is evidence from functional neuroimaging that gambling activates the reward system, similarly, shopping and playing videogames are associated with compulsive behaviors in humans and have also been shown to activate the mesolimbic pathway and other parts of the reward system. Based upon this evidence, gambling addiction, video game addiction, there are a range of genetic and environmental risk factors for developing an addiction that vary across the population. Roughly half of a risk for developing an addiction is derived from genetics. However, even in individuals with a low genetic loading. In other words, anyone can become an addict under the right circumstances, adolescence represents a period of unique vulnerability for developing addiction. Not only are more likely to initiate and maintain drug use. Statistics have shown that those who start to drink alcohol at a younger age are more likely to become dependent later on, about 33% of the population tasted their first alcohol between the ages of 15 and 17, while 18% experienced it prior to this

5.
Intravenous
–
Intravenous therapy is the infusion of liquid substances directly into a vein. Intravenous infusions are commonly referred to as drips, the intravenous route is the fastest way to deliver fluids and medications throughout the body. Intravenous therapy may be used for administration, to correct electrolyte imbalances, to deliver medications. IVs can be categorized by type of vein the tube inserted, called the catheter. A peripheral IV is used on peripheral veins and this is the most common type of IV therapy used. Central IV lines have their catheters that are advanced through a vein and empty into a central vein, usually the superior vena cava. Other advantages are that because it empties near the heart, medications can also be distributed to the rest of the body. As there is room for multiple parallel compartments within the catheter, caregivers can also measure central venous pressure and other physiological variables through the line. They are also longer, which as reflected in Poiseuilles law, requires higher pressure to achieve the same flow, central IV lines carry risks of bleeding, infection, gangrene, thromboembolism and gas embolism. Surrounding structures such as the pleura and carotid artery are also at risk of damage with the potential for pneumothorax or even cannulation of the artery. There are several types of central IVs, depending on the route that the catheter takes from the outside of the body to the vein, typical uses for a PICC include, long chemotherapy regimens, extended antibiotic therapy, or total parenteral nutrition. This is usually done by measuring the distance to a landmark, such as the suprasternal notch. An X-ray must be used to verify that the tip is in the place when fluoroscopy was not used during the insertion. A PICC may have a tube and connector, two or three compartments, each with its own external connector. Power-injectable PICCs are now available as well, from the outside, a single-lumen PICC resembles a peripheral IV, except that the tubing is slightly wider. The insertion site requires better protection than that of a peripheral IV, however, a PICC poses less of a systemic infection risk than other central IVs, because the insertion site is usually cooler and dryer than the sites typically used for other central lines. This helps to slow the growth of bacteria which could reach the bloodstream by traveling under the skin along the outside of the catheter, although special training is required, a PICC does not require the skill level of a physician or surgeon. It is also externally unobtrusive, and with proper hygiene and care can be left in place for months to years if needed for patients who require extended treatment, also, as a PICC travels through the axilla, it can become kinked, causing poor function

6.
Suppository
–
A suppository is a solid dosage form that is inserted into the rectum, vagina or urethra, where it dissolves or melts and exerts local or systemic effects. Suppositories are used to deliver both systemically and locally acting medications, several different ingredients can be used to form the base of a suppository, cocoa butter or a similar substitute, polyethylene glycol, hydrogels and glycerinated gelatin. The type of material used depends on the type of suppository, the type of drug, in 1991, Abd-El-Maeboud and his colleagues conducted a study on suppository insertion in The Lancet, explaining that the torpedo shape helps the device to travel internally, increasing its efficacy. The findings of this study have been challenged as there is insufficient evidence on which to base clinical practice. Alprostadil pellets are urethral suppositories used for the treatment of erectile dysfunction. They are marketed under the name Muse in the United States and its use has diminished since the development of oral impotence medications. Artesunate suppositories Enema Pessary Doyle, D, per Rectum, A History of Enemata, Journal of the Royal College of Physicians of Edinburgh, Vol.35, No.4, pp. 367–370. How Medical Practice Reflects National Culture, The Sciences, Vol.30, No.4, pp. 38–42

7.
Intramuscular injection
–
Intramuscular injection is the injection of a substance directly into a muscle. In medicine, it is one of alternative methods for the administration of medications. Muscles have larger and more vessels than subcutaneous tissue and injections here usually have faster rates of absorption than subcutaneous injections or intradermal injections. Depending on the site, an administration is limited to between 2 and 5 milliliters of fluid. Platelet-rich plasma injections can be administered intramuscularly, certain substances are injected intramuscularly for recreational purposes. Possible sites for IM injection include, deltoid, dorsogluteal, rectus femoris, vastus lateralis, sites that are bruised, tender, red, swollen, inflamed or scarred are avoided. The deltoid muscle site is recommended for use with injections of small volume, usually equal or less than 1 ml and this site is not recommended for repeated injections, due to its small area, it is difficult to rotate the injection site. To locate the site, palpate the lower edge of the acromion process, inject in the upside down triangle that forms with its base at the acromion process and its midpoint in line with the axilla. The ventrogluteal site is recommended for injections requiring a larger volume to be administered, greater than 1 ml and it is also given for narcotic, antibiotic, sedative and anti-emetic medications. To locate the site, place the palm of your hand over the greater trochanter. The right hand is used for the hip and left hand is used for the right hip. Place the index finger on the superior iliac spine and run the middle finger back along the iliac crest. The injection is given in the center of the triangle that is formed, the vastus lateralis site is the recommended site for infants less than 7 months old and those unable to walk, with loss of muscular tone. To locate the site, divide the front thigh into thirds vertically and horizontally to make nine squares and inject in the outer middle square. Use of this site is associated with skin and tissue trauma, muscle fibrosis and contracture, haematoma, nerve palsy and paralysis, as well as infectious processes such as abscess and gangrene. The injection site is located by dividing the buttock into four with a plus shaped cross, the selected site is cleansed with an antimicrobial and is allowed to dry. It is injected with the dominant hand using a quick, darting motion perpendicular to the body at an angle between 72 and 90 degrees, as a faster injection is less painful. The needle is then stabilized with the nondominant hand while the dominant hand slides to the plunger to slowly instill the medication, the CDC does not recommend the outdated practice of aspirating for blood to rule out injecting into a blood vessel

8.
Stimulant
–
Stimulants is an overarching term that covers many drugs including those that increase activity of the body, drugs that are pleasurable and invigorating, or drugs that have sympathomimetic effects. Due to their rendering a characteristic up feeling, stimulants are also referred to as uppers. Depressants or downers, which decrease mental and/or physical function, are in stark contrast to stimulants and are considered to be the functionally opposite drug class, Stimulants are widely used throughout the world as prescription medicines as well as without a prescription as performance-enhancing or recreational drugs. The most frequently prescribed stimulants as of 2013 were lisdexamfetamine, methylphenidate and it is estimated that the percent of the population that has abused amphetamines, cocaine and MDMA combined is between. 8% and 2. 1%. Stimulants in therapeutic doses, such as given to patients with ADHD, increases ability to focus, vigor, sociability, libido. However, in higher doses stimulants may actually decrease the ability to focus, in higher doses stimulants may also produce euphoria, vigor, and decrease need for sleep. Many, but not all, stimulants have ergogenic effects, Drugs such as ephedrine, pseudoephedrine, amphetamine and methylphenidate have well documented ergogenic effects, while drugs such as cocaine and methamphetamine have the opposite effect. In some cases psychiatric phenomenon may emerge such as stimulant psychosis, paranoia, acute toxicity has been reportedly associated with a homicide, paranoia, aggressive behavior, motor dysfunction, and punding. The violent and aggressive behavior associated with acute stimulant toxicity may partially be driven by paranoia, most drugs classified as stimulants are sympathomimetics, that is they stimulate the sympathetic branch of the autonomic nervous system. This leads to such as mydriasis, increased heart rate, blood pressure, respiratory rate. When these changes become pathological, they are called arrhythmia, hypertension, and hyperthermia, however given the complexity of the mechanisms that underly these potentially fatal outcomes of acute stimulant toxicity, it is impossible to determine what dose may be lethal. Assessment of the effects of stimulants is relevant given the large population currently taking stimulants. A systematic review of cardiovascular effects of prescription stimulants found no association in children, a review over a four-year period found that there were few negative effects of stimulant treatment, but stressed the need for longer term studies. A review of a long period of prescription stimulate use in those with ADHD found that cardiovascular side effects were limited to transient increases in blood pressure only. Initiation of stimulant treatment in those with ADHD in early childhood appears to carry benefits into adulthood with regard to social and cognitive functioning, Abuse of prescription stimulants or of illicit stimulants carries many negative health risks. Abuse of cocaine, depending upon route of administration, increases risk of disease, stroke. Cocaine may also increase risk for disease, as well as damage nasal cartilage. Abuse of methamphetamine produces similar effects as well as marked degeneration of dopaminergic neurons, Drugs used to treat sleep disorders such as excessive daytime sleepiness are called eugeroics, and include notable stimulants such as modafinil

9.
Regulation of therapeutic goods
–
The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the level by a single agency. In other jurisdictions they are regulated at the level, or at both state and national levels by various bodies, as is the case in Australia. The role of therapeutic goods regulation is designed mainly to protect the health, regulation is aimed at ensuring the safety, quality, and efficacy of the therapeutic goods which are covered under the scope of the regulation. In most jurisdictions, therapeutic goods must be registered before they are allowed to be marketed, there is usually some degree of restriction of the availability of certain therapeutic goods depending on their risk to consumers. Therapeutic goods in Australia are regulated by the Therapeutic Goods Administration, there are 5 main categories, Normal Medicines - Cough, cold and fever medicines, antiseptics, vitamins and others. Sold freely in pharmacies and some large supermarkets, red Stripe Medicines - These medicines are sold only with medical prescription. Antibiotics, Anti allergenics, Anti inflammatories, and other medicines, in Brazil, governmental control is loose on this type, it is not uncommon to buy this type of prescription medicine over the counter without a prescription. Red Stripe Psychoactive Medicines - These medicines are only with a Special Control white medical prescription with carbon copy. The original must be retained by the pharmacist after the sale, Drugs include anti-depressants, anti-convulsants, some sleep aids, anti-psychotics and other non-habit-inducing controlled medicines. Though some consider them habit inducing, anabolic steroids are also regulated under this category, black Stripe Medicines - These medicines are sold only with the Blue B Form medical prescription, which is valid for 30 days and must be retained by the pharmacist after the sale. Includes sedatives, some anorexic inducers and other habit-inducing controlled medicines, includes amphetamines and other stimulants, opioids and other strong habit-forming controlled medicines. In Canada, regulation of goods are governed by the Food and Drug Act. In addition, the Controlled Drugs and Substances Act requires additional regulatory requirements for controlled drugs, the regulation of drugs in Burma is governed by the Food and Drug Administration and Food and Drug Board of Authority. The regulation of drugs in China is governed by the China Food, Medicines for Human Use in the United Kingdom are regulated by the Medicines and Healthcare products Regulatory Agency. The availability of drugs is regulated by classification by the MHRA as part of marketing authorisation of a product, Medicines in the Republic of Ireland are regulated according to the Misuse of Drugs Regulations 1988. Controlled drugs are divided into five categories based on their potential for misuse, cD1, cannabis, lysergamide, coca leaf, etc. Use prohibited except in limited circumstances where a license has been granted, CD2, amphetamine, methadone, morphine, fentanyl, oxycodone, tapentadol, etc

10.
Misuse of Drugs Act 1975
–
The Misuse of Drugs Act 1975 is a New Zealand drug control law that classifies drugs into three classes, or schedules, based on their projected risk of serious harm of loss of life. The Controlled Substances Classification system has been around for decades but only in 2006 was benzylpiperazine was classified that a substance first became scheduled for health reasons. Most of the controlled substances, such as opium, cocaine. During this conference, the United States were strongly advocating for the banning of these substances unless a scientific or medical use became apparent. New Zealand signed this treaty and its 37th Parliament went on to incorporate this law into the Misuse of Drugs Act 1975, however, the United States did not sign the treaty. ^Note 2, Temazepam and flunitrazepam are subject to legal restrictions. The Expert Advisory Committee on Drugs makes scheduling decisions, based on scientific, national Drug Policy New Zealand notes, The Conventions place certain obligations on signatory countries. When the UN classifies a substance under one of the above Conventions, accordingly, the impetus for some of the drugs to be considered by the EACD will originate from decisions made at the UN

11.
Controlled Substances Act
–
The Controlled Substances Act is the statute establishing federal U. S. drug policy under which the manufacture, importation, possession, use and distribution of certain substances is regulated. It was passed by the 91st United States Congress as Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970, the Act also served as the national implementing legislation for the Single Convention on Narcotic Drugs. The legislation created five Schedules, with varying qualifications for a substance to be included in each, classification decisions are required to be made on criteria including potential for abuse, currently accepted medical use in treatment in the United States, and international treaties. The nation first outlawed addictive drugs in the early 1900s and the International Opium Convention helped lead international agreements regulating trade, the Food and Drugs Act of 1906 was the beginning of over 200 laws concerning public health and consumer protections. Others were the Federal Food, Drug, and Cosmetic Act, in 1969, President Richard Nixon announced that the Attorney General, John N. Shafer—to study cannabis abuse in the United States. It implies an overwhelming indictment of the behavior which we believe is not appropriate, the actual and potential harm of use of the drug is not great enough to justify intrusion by the criminal law into private behavior, a step which our society takes only with the greatest reluctance. According to David T. Courtwright, the Act was part of a reform package designed to rationalize. It eliminated mandatory minimum sentences and provided support for drug treatment, king notes that the rehabilitation clauses were added as a compromise to Senator Jim Hughes, who favored a moderate approach. The bill, as introduced by Senator Everett Dirksen, ran to 91 pages, since its enactment in 1970, the Act has been amended several times, The Medical Device Amendments of 1976. The Psychotropic Substances Act of 1978 added provisions implementing the Convention on Psychotropic Substances, the Controlled Substances Penalties Amendments Act of 1984. The Ryan Haight Online Pharmacy Consumer Protection Act of 2008 The Electronic Prescriptions for Controlled Substances 2010, the Controlled Substances Act consists of 2 subchapters. Subchapter II describes the laws for exportation and importation of controlled substances, again specifying fines, the Drug Enforcement Administration was established in 1973, combining the Bureau of Narcotics and Dangerous Drugs and Customs drug agents. When a petition is received by the DEA, the agency begins its own investigation of the drug and this request is sent to the Assistant Secretary of Health of HHS. Under certain circumstances, the Government may temporarily schedule a drug without following the normal procedure, an example is when international treaties require control of a substance. In addition,21 U. S. C. §811 allows the Attorney General to temporarily place a substance in Schedule I to avoid an imminent hazard to the public safety, in any case, once these proceedings are complete, the temporary order is automatically vacated. Unlike ordinary scheduling proceedings, such orders are not subject to judicial review. The CSA also creates a system of distribution for those authorized to handle controlled substances. The cornerstone of this system is the registration of all those authorized by the DEA to handle controlled substances

12.
Convention on Psychotropic Substances
–
The Single Convention on Narcotic Drugs of 1961 could not ban the many newly discovered psychotropics, since its scope was limited to drugs with cannabis, coca, and opium-like effects. The Convention, which contains import and export restrictions and other rules aimed at limiting drug use to scientific and medical purposes, as of 2013,183 member states are Parties to the treaty. Many laws have passed to implement the Convention, including the U. S. Psychotropic Substances Act, the UK Misuse of Drugs Act 1971. Adolf Lande, under the direction of the United Nations Office of Legal Affairs, the Commentary, published in 1976, is an invaluable aid to interpreting the treaty and constitutes a key part of its legislative history. This treaty, signed in 1988, regulates precursor chemicals to drugs controlled by the Single Convention and it also strengthens provisions against money laundering and other drug-related crimes. International drug control began with the 1912 International Opium Convention, a treaty which adopted import and export restrictions on the opium poppys psychoactive derivatives, after the United Nations was formed in 1945, those enforcement functions passed to the UN. During the 1960s, drug use increased in Western developed nations, young people began using hallucinogenic, stimulant, and other drugs on a widespread scale that has continued to the present. In many jurisdictions, police had no laws under which to prosecute users and traffickers of these new drugs, LSD, the language of the Single Convention and its legislative history precluded any interpretation that would allow international regulation of these drugs under that treaty. A new convention, with a scope, would be required in order to bring those substances under control. Using the Single Convention as a template, the Commission prepared a draft convention which was forwarded to all UN member states, the Secretary-General of the United Nations scheduled a conference for early 1971 to finalize the treaty. Meanwhile, countries had already begun passing legislation to implement the draft treaty, in 1969, Canada added Part IV to its Food and Drugs Act, placing a set of restricted substances, including LSD, DMT, and MDA, under federal control. In 1970, the United States completely revamped its existing drug laws by enacting the Controlled Substances Act. In 1971, the United Kingdom passed the Misuse of Drugs Act 1971, a host of other nations followed suit. The conference convened on 11 January 1971, Nations split into two rival factions, based on their interests. According to a Senate of Canada report, One group included mostly developed nations with powerful pharmaceutical industries, the other group consisted of developing states. with few psychotropic manufacturing facilities. The organic drugmaking states that had suffered economically from the Single Conventions restrictions on cannabis, coca, the synthetic drug-producing states opposed those restrictions. The Conventions adoption marked a milestone in the development of the global drug control regime. As of June 2013, there are 183 state parties to the convention and this total includes 182 member states of the United Nations and the Holy See

13.
Pharmacokinetics
–
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered to a living organism. The substances of interest include any chemical xenobiotic such as, pharmaceutical drugs, pesticides, food additives, cosmetic ingredients, etc. It attempts to analyze chemical metabolism and to discover the fate of a chemical from the moment that it is administered up to the point at which it is eliminated from the body. Pharmacokinetics is the study of how an organism affects a drug, both together influence dosing, benefit, and adverse effects, as seen in PK/PD models. Pharmacokinetic properties of chemicals are affected by the route of administration and these may affect the absorption rate. Models have been developed to simplify conceptualization of the processes that take place in the interaction between an organism and a chemical substance. The various compartments that the model is divided into are commonly referred to as the ADME scheme, absorption - the process of a substance entering the blood circulation. Distribution - the dispersion or dissemination of substances throughout the fluids, metabolism – the recognition by the organism that a foreign substance is present and the irreversible transformation of parent compounds into daughter metabolites. Excretion - the removal of the substances from the body, in rare cases, some drugs irreversibly accumulate in body tissue. The two phases of metabolism and excretion can also be grouped together under the title elimination, the study of these distinct phases involves the use and manipulation of basic concepts in order to understand the process dynamics. All these concepts can be represented through mathematical formulas that have a graphical representation. The model outputs for a drug can be used in industry or in the application of pharmacokinetic concepts. Clinical pharmacokinetics provides many performance guidelines for effective and efficient use of drugs for human-health professionals, in practice, it is generally considered that steady state is reached when a time of 4 to 5 times the half-life for a drug after regular dosing is started. Noncompartmental methods estimate the exposure to a drug by estimating the area under the curve of a concentration-time graph, compartmental methods estimate the concentration-time graph using kinetic models. Noncompartmental methods are more versatile in that they do not assume any specific compartmental model. The final outcome of the transformations that a drug undergoes in an organism, a number of functional models have been developed in order to simplify the study of pharmacokinetics. These models are based on a consideration of an organism as a number of related compartments, the simplest idea is to think of an organism as only one homogenous compartment. However, these models do not always reflect the real situation within an organism

14.
Bioavailability
–
By definition, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes, its bioavailability generally decreases or may vary from patient to patient, Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered when calculating dosages for non-intravenous routes of administration. Bioavailability is defined differently for drugs as opposed to dietary supplements primarily due to the method of administration and Food. Bioaccessibility is a related to bioavailability in the context of biodegradation. A molecule is said to be bioaccessible when is available to cross a cellular membrane from the environment. In pharmacology, bioavailability is a measurement of the rate and extent to which a drug reaches at the site of action and it is denoted by the letter f. Therefore, bioavailability for dietary supplements can be defined as the proportion of the administered substance capable of being absorbed, in both pharmacology and nutrition sciences, bioavailability is measured by calculating the area under curve of the drug concentration time profile. Bioavailability is commonly a factor in the production of crops. Toxic materials in soil, such as lead from paint may be rendered unavailable to animals ingesting contaminated soil by supplying phosphorus fertilizers in excess and it is the fraction of the drug absorbed through non-intravenous administration compared with the corresponding intravenous administration of the same drug. The comparison must be normalized, consequently, the amount absorbed is corrected by dividing the corresponding dose administered. The absolute bioavailability is the area under curve non-intravenous divided by AUC intravenous. For example, the formula for calculating F for a drug administered by the route is given below. If we compare the two different dosage forms having same active ingredients and compare the two drug bioavailability is called comparative bioavailability, although knowing the true extent of systemic absorption is clearly useful, in practice it is not determined as frequently as one may think. The reason for this is that its assessment requires a reference, that is. These limitations may be overcome, however, by administering a low dose of an isotopically labelled drug concomitantly with a therapeutic non-labelled oral dose. This technique eliminates pharmacokinetic issues on non-equivalent clearance as well as enabling the intravenous dose to be administered with a minimum of toxicology, the technique was first applied using stable-isotopes such as 13C and mass-spectrometry to distinguish the isotopes by mass difference. More recently, 14C labelled drugs are administered intravenously and accelerator mass spectrometry used to measure the isotopically labelled drug along with mass spectrometry for the unlabelled drug, in all such cases, to conduct an absolute bioavailability study requires that the drug be given intravenously. Intravenous administration of a drug can provide valuable information on the fundamental pharmacokinetic parameters of volume of distribution

15.
Drug metabolism
–
Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. These pathways are a form of biotransformation present in all groups of organisms. These reactions often act to detoxify poisonous compounds, the study of drug metabolism is called pharmacokinetics. The metabolism of drugs is an important aspect of pharmacology. For example, the rate of metabolism determines the duration and intensity of a drugs pharmacologic action, the enzymes of xenobiotic metabolism, particularly the glutathione S-transferases are also important in agriculture, since they may produce resistance to pesticides and herbicides. Drug metabolism is divided into three phases, in phase I, enzymes such as cytochrome P450 oxidases introduce reactive or polar groups into xenobiotics. These modified compounds are conjugated to polar compounds in phase II reactions. These reactions are catalysed by enzymes such as glutathione S-transferases. Finally, in phase III, the conjugated xenobiotics may be processed, before being recognised by efflux transporters. Drug metabolism often converts lipophilic compounds into hydrophilic products that are readily excreted. The exact compounds an organism is exposed to will be unpredictable, and may differ widely over time. The solution that has evolved to address this problem is an elegant combination of physical barriers, all organisms use cell membranes as hydrophobic permeability barriers to control access to their internal environment. This selective uptake means that most hydrophilic molecules cannot enter cells, in contrast, the diffusion of hydrophobic compounds across these barriers cannot be controlled, and organisms, therefore, cannot exclude lipid-soluble xenobiotics using membrane barriers. However, the existence of a permeability barrier means that organisms were able to evolve detoxification systems that exploit the hydrophobicity common to membrane-permeable xenobiotics and these systems therefore solve the specificity problem by possessing such broad substrate specificities that they metabolise almost any non-polar compound. Useful metabolites are excluded since they are polar, and in general one or more charged groups. However, since these compounds are few in number, specific enzymes can recognize, the metabolism of xenobiotics is often divided into three phases, - modification, conjugation, and excretion. These reactions act in concert to detoxify xenobiotics and remove them from cells, in phase I, a variety of enzymes act to introduce reactive and polar groups into their substrates. One of the most common modifications is hydroxylation catalysed by the cytochrome P-450-dependent mixed-function oxidase system and these enzyme complexes act to incorporate an atom of oxygen into nonactivated hydrocarbons, which can result in either the introduction of hydroxyl groups or N-, O- and S-dealkylation of substrates

16.
Dopamine beta-hydroxylase
–
Dopamine beta-hydroxylase, also known as dopamine beta-monooxygenase, is an enzyme that in humans is encoded by the DBH gene. DBH is a 290 kDa copper-containing oxygenase consisting of four identical subunits and it is the only enzyme involved in the synthesis of small-molecule neurotransmitters that is membrane-bound, making norepinephrine the only known transmitter synthesized inside vesicles. It is expressed in nerve terminals of the central and peripheral nervous systems. Based on the observations of what happens when theres no substrate, or oxygen, although details of DBH mechanism are yet to be confirmed, DBH is homologous to another enzyme, peptidylglycine α-hydroxylating monooxygenase. Because DBH and PHM share similar structures, it is possible to model DBH mechanism based on what is known about PHM mechanism, dopamine beta-hydroxylase catalyzes the hydroxylation of not only dopamine but also other phenylethylamine derivatives when available. The minimum requirement seems to be a ring with a two-carbon side chain that terminates in an amino group. DBH primarily contributes to catecholamine and trace amine biosynthesis, inadequate DBH is called dopamine beta hydroxylase deficiency. Because it is difficult to obtain a stable crystal of dopamine beta-hydroxylase, however, an homology model based on the primary sequence and comparison to PHM is available. This protein may use the model of allosteric regulation. DBH is inhibited by disulfiram, tropolone, and, most selectively, DBH is reversibly inhibited by l-2H-Phthalazine hydrazone, 2-1H-pyridinone hydrazone, 2-quinoline-carboxylic acid, l-isoquinolinecarboxylic acid,2, 2-bi-lH-imidazole, and IH-imidazole-4-acetic acid. HYD, QCA, and IAA are allosteric competitive, the systematic name of this enzyme class is 3, 4-dihydroxyphenethylamine, ascorbate, oxygen oxidoreductase

17.
4-Hydroxyamphetamine
–
It is used medically in eye drops to dilate the pupil, so that the back of the eye can be examined. It is also a metabolite of amphetamine and certain substituted amphetamines. 4-Hydroxyamphetamine is used in eye drops to dilate the pupil so that the back of the eye can be examined and this is a diagnostic test for Horners Syndrome. Patients with Horner’s syndrome exhibit anisocoria brought about by lesions on the nerves that connect to the branch of the ophthalmic nerve. Application of 4-hydroxyamphetamine to the eye can indicate whether the lesion is preganglionic or postganglionic based on the pupil’s response, if the pupil dilates, the lesion is preganglionic. If the pupil does not dilate, the lesion is postganglionic, 4-hydroxyamphetamine has some limitations to its use as a diagnostic tool. If it is intended as a follow up to another mydriatic drug. It also has the tendency to falsely localize lesions, like amphetamine, 4-hydroxyamphetamine is an agonist of human TAAR1. 4-Hydroxyamphetamine acts as an indirect sympathomimetic and causes the release of norepinephrine from nerve synapses which leads to mydriasis, in humans, amphetamine is metabolized to 4-hydroxyamphetamine by CYP2D6, which is a member of the cytochrome P450 superfamily and is found in the liver. 4-Hydroxyamphetamine is then metabolized by dopamine beta-hydroxylase into 4-hydroxynorephedrine or eliminated in the urine, hydroxyamphetamine is a component of two controlled, name-brand ophthalmic mydriatics, Paredrine and Paremyd. Paredrine consists of a 1% solution of hydroxyamphetamine hydrobromide while Paremyd consists of a combination of 1% hydroxyamphetamine hydrobromide and 0. 25% tropicamide. Around 1997, Akorn, Inc. obtained the rights to both Paredrine and Paremyd, and in 2002, the company reintroduced Paremyd to the market as a fast acting ophthalmic mydriatic agent, amphetamine Pholedrine Tyramine p-Hydroxyamphetamine at the US National Library of Medicine Medical Subject Headings

18.
Hippuric acid
–
Hippuric acid is a carboxylic acid found in the urine of horses and other herbivores. Hippuric acid crystallizes in rhombic prisms which are soluble in hot water, melt at 187 °C. When many aromatic compounds such as acid and toluene are taken internally, they are converted to hippuric acid by reaction with the amino acid. A modern synthesis of hippuric acid involves the acylation of glycine with benzoyl chloride, Hippuric acid is readily hydrolysed by hot caustic alkalis to benzoic acid, nitrous acid converts it into benzoyl glycolic acid, C6H5COCH2CO2H. Its ethyl ester reacts with hydrazine to form hippuryl hydrazine, C6H5CONHCH2CONHNH2 and it was also formed by heating benzoic anhydride with glycine, and by heating benzamide with monochloroacetic acid. Aminohippuric acid Ortho-iodohippurate This article incorporates text from a now in the public domain, Chisholm, Hugh

19.
Phenylpropanolamine
–
It is commonly used in prescription and over-the-counter cough and cold preparations. In veterinary medicine, it is used to control urinary incontinence in dogs under trade names Propalin and Proin, in the United States, PPA is no longer sold due to a purported increased risk of stroke in younger women. In a few countries in Europe, however, it is available either by prescription or sometimes over-the-counter. In Canada, it was withdrawn from the market on 31 May 2001, in India human use of PPA and its formulations was banned on 10 February 2011, but the ban was overturned by the judiciary in September 2011. Phenylpropanolamine acts as a receptor and beta-adrenergic receptor agonist as well as a dopamine receptor D1 partial agonist. In Europe, PPA is still available in prescription decongestants such as Rinexin, as of 11 August, a European Category 1 Licence is required to purchase PPA for academic use. In the United States, the Food and Drug Administration issued a health advisory against the use of the drug in November 2000. In this advisory, the FDA requested that all drug companies discontinue marketing products containing PPA, the agency estimates that PPA caused between 200 and 500 strokes per year among 18-to-49-year-old users. In 2005, the FDA removed PPA from over-the-counter sale, because of its potential use in amphetamine manufacture, it is controlled by the Combat Methamphetamine Epidemic Act of 2005. It is still available for use in dogs, however. Drugs containing PPA were banned in India on 27 January 2011, on 13 September 2011 Madras High Court revoked a ban on manufacture and sale of paediatric drugs nimesulide and phenylpropanolamine. There are four isomers of PPA, dextro- and levo-norephedrine. D-Norpseudoephedrine is also known as cathine, and occurs naturally in Catha edulis, the methyl group on the alpha carbon also makes this compound a member of the substituted amphetamine class. Ephedrine is the N-methyl analogue of phenylpropanolamine, exogenous compounds in this family are degraded too rapidly by monoamine oxidase to be active at all but the highest doses. However, the addition of the group allows the compound to avoid metabolism. In general, N-methylation of primary amines increases their potency, whereas β-hydroxylation decreases CNS activity, but conveys more selectivity for adrenergic receptors

20.
Phenylacetone
–
Phenylacetone is an organic compound with the chemical formula C6H5CH2CCH3. It is an oil that is soluble in organic solvents. This substance is used in the manufacture of methamphetamine and amphetamine, due to the illicit uses in clandestine chemistry, it was declared a schedule II controlled substance in the United States in 1980. In humans, phenylacetone occurs as a metabolite of amphetamine and methamphetamine via FMO3-mediated oxidative deamination, mDP2P - related compound with a methylenedioxy group, and a precursor to MDMA. Cyclohexylacetone - the cyclohexane derivative of phenylacetone Phenylacetones Methamphetamine

21.
PH
–
In chemistry, pH is a numeric scale used to specify the acidity or basicity of an aqueous solution. It is approximately the negative of the base 10 logarithm of the concentration, measured in units of moles per liter. More precisely it is the negative of the logarithm to base 10 of the activity of the hydrogen ion, solutions with a pH less than 7 are acidic and solutions with a pH greater than 7 are basic. Pure water is neutral, at pH7, being neither an acid nor a base, contrary to popular belief, the pH value can be less than 0 or greater than 14 for very strong acids and bases respectively. The pH scale is traceable to a set of standard solutions whose pH is established by international agreement, the pH of aqueous solutions can be measured with a glass electrode and a pH meter, or an indicator. In the first papers, the notation had the H as a subscript to the p, as so. The exact meaning of the p in pH is disputed, but according to the Carlsberg Foundation and it has also been suggested that the p stands for the German Potenz, others refer to French puissance. Another suggestion is that the p stands for the Latin terms pondus hydrogenii, potentia hydrogenii and it is also suggested that Sørensen used the letters p and q simply to label the test solution and the reference solution. Currently in chemistry, the p stands for decimal cologarithm of, PH is defined as the decimal logarithm of the reciprocal of the hydrogen ion activity, aH+, in a solution. P H = − log 10 ⁡ = log 10 ⁡ For example and this definition was adopted because ion-selective electrodes, which are used to measure pH, respond to activity. For H+ number of electrons transferred is one and it follows that electrode potential is proportional to pH when pH is defined in terms of activity. The reference electrode may be a silver chloride electrode or a calomel electrode, the hydrogen-ion selective electrode is a standard hydrogen electrode. Reference electrode | concentrated solution of KCl || test solution | H2 | Pt Firstly, the cell is filled with a solution of hydrogen ion activity. Then the emf, EX, of the cell containing the solution of unknown pH is measured. PH = pH + E S − E X z The difference between the two measured emf values is proportional to pH and this method of calibration avoids the need to know the standard electrode potential. The proportionality constant, 1/z is ideally equal to 12.303 R T / F the Nernstian slope, to apply this process in practice, a glass electrode is used rather than the cumbersome hydrogen electrode. A combined glass electrode has a reference electrode. It is calibrated against buffer solutions of hydrogen ion activity

22.
Pharmacodynamics
–
Pharmacodynamics is the study of the biochemical and physiologic effects of drugs. The effects can include those manifested within animals, microorganisms, or combinations of organisms, Pharmacodynamics is the study of how a drug affects an organism, whereas pharmacokinetics is the study of how the organism affects the drug. Both together influence dosing, benefit, and adverse effects, Pharmacodynamics is sometimes abbreviated as PD and pharmacokinetics as PK, especially in combined reference. Pharmacodynamics places particular emphasis on relationships, that is, the relationships between drug concentration and effect. One dominant example is drug-receptor interactions as modeled by L + R ⇌ L ⋅ R where L, R, and LR represent ligand, receptor and this equation represents a simplified model of reaction dynamics that can be studied mathematically through tools such as free energy maps. Antacids and chelating agents combine chemically in the body, the widest class of drugs act as ligands which bind to receptors which determine cellular effects. Upon drug binding, receptors can elicit their normal action, blocked action, in principle, a pharmacologist would aim for a target plasma concentration of the drug for a desired level of response. In reality, there are factors affecting this goal. Pharmacokinetic factors determine peak concentrations, and concentrations cannot be maintained with absolute consistency because of metabolic breakdown, genetic factors may exist which would alter metabolism or drug action itself, and a patients immediate status may also affect indicated dosage. The duration of action of a drug is the length of time that particular drug is effective, the binding of ligands to receptors is governed by the law of mass action which relates the large-scale status to the rate of numerous molecular processes. The rates of formation and un-formation can be used to determine the concentration of bound receptors. The equilibrium dissociation constant is defined by, L + R ↔ L ⋅ R K d = where L=ligand, R=receptor, the fraction of bound receptors is known as occupancy. The relationship between occupancy and pharmacological response is usually non-linear and this explains the so-called receptor reserve phenomenon i. e. the concentration producing 50% occupancy is typically higher than the concentration producing 50% of maximum response. The simplest interpretation of receptor reserve is that it is a model that states there are excess receptors on the surface than what is necessary for full effect. Thus, the existence of receptor reserve depends on the agonist, tissue, as receptor reserve is very sensitive to agonist’s intrinsic efficacy, it is usually defined only for full agonists. Often the response is determined as a function of log to consider many orders of magnitude of concentration, however, there is no biological or physical theory which relates effects to the log of concentration. It is just convenient for graphing purposes and it is useful to note that 50% of the receptors are bound when =Kd. The graph shown represents the conc-response for two hypothetical receptor agonists, plotted in a semi-log fashion, the curve toward the left represents a higher potency since lower concentrations are needed for a given response

Graph that demonstrates the Michaelis–Menten kinetics model for the relationship between an enzyme and a substrate: one of the parameters studies in pharmacokinetics, where the substrate is a pharmaceutical drug.

Different forms of tablets, which will have different pharmacokinetic behaviours after their administration.

The time course of drug plasma concentrations over 96 hours following oral administrations every 24 hours. Note that the AUC in steady state equals AUC∞ after the first dose.

Dopamine beta-hydroxylase (DBH), also known as dopamine beta-monooxygenase, is an enzyme (EC 1.14.17.1) that in humans …

In the absence of oxygen, dopamine or other substrates, the enzyme and ascorbate mixture produces reduced enzyme and dehydroascorbate. Exposing the reduced enzyme to oxygen and dopamine results in oxidation of the enzyme and formation of noradrenaline and water, and this step doesn't require ascorbate.

Image: Models for Oligomer Structures of DBH

Dopamine is converted to norepinephrine by the enzyme dopamine β-hydroxylase. Ascorbic acid serves as a cofactor.

In the field of pharmacology, potency is a measure of drug activity expressed in terms of the amount required to …

Concentration-response curves illustrating the concept of potency. For a response of 0.25a.u., Drug B is more potent, as it generates this response at a lower concentration. For a response of 0.75a.u., Drug A is more potent. a.u. refers to "arbitrary units".